PROJECT SUMMARY DROSOPHILA CORE The goal of the Drosophila Core (DC) of the Model Organism Screening Center (MOSC) is to provide in vivo functional information for evolutionarily conserved genes and variants that are likely to underlie specific pathological phenotypes of UDN patients. This will support the molecular diagnosis and facilitate the development of potential therapeutic strategies for rare diseases. To accomplish this goal, the leadership team proposes to use numerous novel strategies, technologies and transgenic strains. Using these tools, our DC will rapidly generate strong loss-of-function (LOF) alleles of potential disease associated genes in Drosophila and characterize their phenotypes. Next, we will determine if the human homolog can rescue these phenotypes to provide a strong molecular link between the Drosophila and human homologs. If rescue is obtained, we will examine the effect of the UDN variants. We will further characterize expression patterns and assess subcellular localization of proteins using the MiMIC and CRIMIC technologies, a novel gene/protein tagging strategy that we recently developed. For genes that have strong LOF phenotypes that can be rescued by the human cDNA, we will perform detailed secondary phenotypic analyses to determine the role of the gene/protein in the organ systems that are affected in the UDN human patients. The proposed pipeline will be highly cost efficient compared to many other options, and will generate high-quality reproducible data in Drosophila that can be directly or indirectly linked to human disease phenotypes.